Obesity may be the major health problem of the Western world. Nearly 20% of the United States' adult population is overweight and its prevalence is rising. The medical and economic importance of obesity go far beyond effects on self-image. Obesity is the dominant risk factor for the expression of adult-onset diabetes mellitus, and thus leads to complications of cardiovascular, renal, and peripheral vascular disease. Obesity is also a leading factor in the development of complications after surgical procedures.
Although obesity is probably a common endpoint for a variety of disorders, all causes of obesity have at least a period of hyperphagia in which the subject eats more food than needed for the current energy needs. Currently, there is no effective treatment for hyperphagia. The agents used, at best, work for only a few weeks or are clinically unsafe because of serious side effects.
This invention teaches the use of DHEA and one or more of the following anorectic agents for the treatment of obesity and related disorders in animals: fenfluramine hydrochloride (HCl), phentermine HCl, phendimetrazine tartrate, mazindol, diethylpropion HCl, and fluoxetine HCl. DHEA has been evaluated for its ability to modify food intake and/or weight when administered individually, but not in combination with the anorectic drugs disclosed in this invention. There was no appreciation in the art that the combined use of DHEA and one or more of the disclosed anorectic agents would have a significant and dramatic effect on the treatment of obesity and related disorders.
Dehydroepiandrosterone (DHEA) and its sulphated derivative, both major secretory products of the human adrenal, are naturally occurring steroids. Traditionally, DHEA has been called an adrenal androgen because it can be metabolized in the periphery to testosterone. DHEA itself cannot interact with the androgen receptor, and thus is not an androgen.
The effect of DHEA on food intake and obesity in the Zucker rat was studied by Cleary M. P., "The Antiobesity Effect of Dehydroepiandrosterone in Rats," Proceedings of the Society for Experimental Biology and Medicine, 196:8-16 (1991). This reference reports results showing administration of DHEA to rats caused a weight loss independent of food intake. Conflicting reports have been reported by others, who found that administration of DHEA decreased caloric intake in obese Zucker rats, but not in the lean animal. Wright et al., "Divergent Effect of Dehydroepiandrosterone on Energy Intakes of Zucker Rats," Physiology & Behavior, 53:39-43 (1993). The conflicting reports may reflect the different methods employed by the two groups in calculating food intake for the animals. Cleary measured daily cumulative food intake, in which changes are measured at the end of a period of time such as two weeks. Wright et al. measured daily intake and weight change for 7-8 days. An initial change was found within 24 hours. As the animals' weight and metabolism may have already changed with administration of the drug at the end of a two week period, the method of Wright et al. more clearly reflects the effect of the drug on the animal.
DHEA was also evaluated for its effect on obesity, serum lipids, and body fat in humans. Nestler et al., "Dehydroepiandrosterone Reduces Serum Low Density Lipoprotein Levels and Body Fat but Does not Alter Insulin Sensitivity in Normal Men," J. Clin. Endocrinol. Metab., 66:57-61 (1988). Results showed DHEA in a divided dose of 1600 mg/person/day, corresponding to a dose of about 22 mg/kg/day, has no effect on either food intake or body weight in lean subjects, although it may have a slight effect on body fat content. Other researchers were unable to repeat the positive results. Welle et al., "Failure of Dehydroepiandrosterone to Influence Energy and Protein Metabolism in Humans," Journal of Clinical Endocrintogy, 71:1259-1264 (1990).
The anorectic drugs used in this invention include fenfluramine HCl, phentermine HCl, phendimetrazine tartrate, mazindol, diethylpropion HCl, and fluoxetine HCl. Tachyphylaxis and tolerance have been demonstrated with all drugs of this class used in the treatment of obesity. Physician's Desk Reference., 47th edition, page 1053 (Medical Economics Data, Montvale, N.J., 1993), incorporated by reference. It has not been established that the action of such drugs in treating obesity is primarily one of appetite suppression, as other central nervous system actions or metabolic effects may be involved. Physician's Desk Reference at 1053. The drugs are not particularly effective, as the magnitude of increased weight loss of drug-treated patients over placebo-treated patients is only a fraction of a pound a week, with the rate of weight loss being greatest in the first weeks of therapy for both drug and placebo-treated subjects and decreasing in succeeding weeks as tolerance to the anorectic agent develops. Physician's Desk Reference at 1053.
Fenfluramine HCl, chemically known as N-ethyl-.alpha.-methyl-3(tri-fluoromethyl)benzeneethanamine hydrochloride, is an anorectic agent differing from prototype anorectic drugs used in the treatment of obesity in appearing to produce more central nervous system depression than stimulation. Physician's Desk Reference at 1949. Tolerance to the anorectic effect usually develops within a few weeks, requiring discontinuation of the use of the drug. Physician's Desk Reference at 1949. The drug is commercially available under the trade name PONDIMIN.RTM. Tablets (A. H. Robins Co.).
Phentermine hydrochloride, chemically known as phenyltertiary-butylamine hydrochloride, is a sympathomimetic amine with pharmacologic activity similar to the prototype drugs of this class used in obesity, the amphetamines. Physician's Desk Reference at 1053 and 2305. The drug is an anorectic compound with actions including central nervous system stimulation and elevation of blood pressure. Physician's Desk Reference at 1053. Tolerance to the anorectic effect usually develops within a few weeks, requiring discontinuation of the use of the drug. Physician's Desk Reference at 1053. The drug is commercially available under the trade names FASTIN.RTM. Capsules (SmithKline Beecham Pharmaceuticals) and ADIPEX-P.RTM. (Gate Pharmaceuticals).
Phendimetrazine tartrate, chemically known as (+)-3,4-dimethyl-2-phenylmorpholine tartrate, is another anorectic drug having an effect on appetite and the central nervous system. Physician's Desk Reference at 710, 857, and 2618. Tolerance to the anorectic effect usually develops within a few weeks, requiring discontinuation of the use of the drug. Physician's Desk Reference at 711. The drug is commercially available under the trade names PRELU-2.RTM. (Boehringer Ingelheim Pharmaceuticals, Inc.), BONTRIL.RTM. PDM and BONTRIL.RTM. SLOW-RELEASE (Carnrick Laboratories, Inc.), and PLEGINE.RTM. (Wyeth-Ayerst Laboratories).
Mazindol, chemically designated as 5-(4-chlorophenyl)-2,5-dihydro-3H-imidazo[2,1-.alpha.]isoindol-5-ol, is an imidazoisoindole anorectic agent. Physician's Desk Reference at 2126. Although an isoindole, mazindol has pharmacologic activity similar to the prototype drugs used in obesity, the amphetamines. Physician's Desk Reference at 2126. Tolerance to the anorectic effect usually develops within a few weeks, requiring discontinuation of the use of the drug. Physician's Desk Reference at 2127. The drug is commercially available under the trade name SANOREX.RTM. (Sandoz Pharmaceuticals Corp.).
Diethylpropion hydrochloride, chemically known as 1-phenyl-2-diethylamino-1-propanone hydrochloride, is a sympathomimetic amine with actions including some central nervous system stimulation and elevation of blood pressure. Physician's Desk Reference at 1403. Tolerance to the anorectic effect usually develops within a few weeks, at which point the drug is discontinued. Physician's Desk Reference at 1403. Diethylpropion HCl is commercially available under the trade names TENUATE.RTM. and TENUATE DOSPAN.RTM. (Marion Merrell Dow Inc.).
Finally, fluoxetine HCl, chemically designated (.+-.)-N-methyl-3-phenyl-3-[(.alpha.,.alpha.,.alpha.-trifluro-p-tolyl)oxy] propylamine hydrochloride, is a compound used as an antidepressant. Physician's Desk Reference at 943. The drug influences serotonergic transmission, a characteristic of anorectic agents. Van de Kar et al., "Serotonergic Neurons and Neuroendocrine Function," NIPS, 8:202-207 (1993). Significant weight loss can result with fluoxetine HCl treatment. Physician's Desk Reference at 944; Darga et al., "Fluoxetine's Effect on Weight Loss in Obese Subjects," Am. J. Clin. Nutr., 54:321-5 (1991); and Visser et al., "The Effect of Fluoxetine on Body Weight, Body Composition and Visceral Fat Accumulation," Int. J. Obes., 17:247-53 (1993). Fluoxetine HCl has not been systematically studied, in animals or humans, for its potential for tolerance. Physician's Desk Reference at 945-6. However, recent studies showed rapid development of tolerance with administration of fluoxetine and fenfluramine. McGuirk et al., "Effects of Chronically Administered Fluoxetine and Fenfluramine on Food Intake, Body Weight and the Behavioural Satiety Sequence," Psychopharmocology (Berl), 106:401-7 (1992). The drug is commercially available under the trade name PROZAC.RTM. (Dista Products Co.).
This invention fulfils a need in the art for an effective method for treating obesity and related disorders in animals. The method, employing a composition comprising DHEA or a derivative thereof and an anorectic agent, diminishes caloric intake, may affect metabolism, or a combination thereof, to produce a weight loss for the treated subject. Other objects and advantages of the invention are set forth in the following description. The accompanying drawings illustrate and, together with this description, explain the principle of the invention.